Molecular mechanisms of resistance to the EGFR monoclonal antibody cetuximab (original) (raw)

1. Carpenter G, Lembach KJ, Morrison MM, Cohen S. Characterization of the binding of 125I-labeled epidermal growth factor to human fibroblasts. J Biol Chem. 1975;250:4297–4304. [PubMed] [Google Scholar]

2. Carpenter G, King L, Jr, Cohen S. Epidermal growth factor stimulates phosphorylation in membrane preparations in vitro. Nature. 1978;276:409–410. [PubMed] [Google Scholar]

3. Ullrich A, Coussens L, Hayflick JS, Dull TJ, Gray A, Tam AW, et al. Human epidermal growth factor receptor cDNA sequence and aberrant expression of the amplified gene in A431 epidermoid carcinoma cells. Nature. 1984;309:418–425. [PubMed] [Google Scholar]

4. Eckhart W, Hutchinson MA, Hunter T. An activity phosphorylating tyrosine in polyoma T antigen immunoprecipitates. Cell. 1979;18:925–933. [PubMed] [Google Scholar]

5. Hunter T, Sefton BM. Transforming gene product of Rous sarcoma virus phosphorylates tyrosine. Proc Natl Acad Sci USA. 1980;77:1311–1315. [PMC free article] [PubMed] [Google Scholar]

6. Riedel H, Dull TJ, Schlessinger J, Ullrich A. A chimaeric receptor allows insulin to stimulate tyrosine kinase activity of epidermal growth factor receptor. Nature. 1986;324:68–70. [PubMed] [Google Scholar]

7. Schlessinger J. Signal transduction by allosteric receptor oligomerization. Trends Biochem Sci. 1988;13:443–447. [PubMed] [Google Scholar]

8. Yarden Y, Sliwkowski MX. Untangling the ErbB signalling network. Nat Rev Mol Cell Biol. 2001;2:127–137. [PubMed] [Google Scholar]

9. Hynes NE, Lane HA. ERBB receptors and cancer: the complexity of targeted inhibitors. Nat Rev Cancer. 2005;5:341–354. [PubMed] [Google Scholar]

10. Klapper LN, Glathe S, Vaisman N, Hynes NE, Andrews GC, Sela M, et al. The ErbB-2/HER2 oncoprotein of human carcinomas may function solely as a shared coreceptor for multiple stroma-derived growth factors. Proc Natl Acad Sci USA. 1999;96:4995–5000. [PMC free article] [PubMed] [Google Scholar]

11. Singh AB, Harris RC. Autocrine, paracrine and juxtacrine signaling by EGFR ligands. Cell Signal. 2005;17:1183–1193. [PubMed] [Google Scholar]

12. Baselga J, Swain SM. Novel anticancer targets: revisiting ERBB2 and discovering ERBB3. Nat Rev Cancer. 2009;9:463–475. [PubMed] [Google Scholar]

13. Guy PM, Platko JV, Cantley LC, Cerione RA, Carraway KL., 3rd Insect cell-expressed p180erbB3 possesses an impaired tyrosine kinase activity. Proc Natl Acad Sci USA. 1994;91:8132–8136. [PMC free article] [PubMed] [Google Scholar]

14. Wallasch C, Weiss FU, Niederfellner G, Jallal B, Issing W, Ullrich A. Heregulin-dependent regulation of HER2/neu oncogenic signaling by heterodimerization with HER3. EMBO J. 1995;14:4267–4275. [PMC free article] [PubMed] [Google Scholar]

15. Sebolt-Leopold JS, Herrera R. Targeting the mitogen-activated protein kinase cascade to treat cancer. Nat Rev Cancer. 2004;4:937–947. [PubMed] [Google Scholar]

16. Engelman JA. Targeting PI3K signalling in cancer: opportunities, challenges and limitations. Nat Rev Cancer. 2009;9:550–562. [PubMed] [Google Scholar]

17. Carpenter G, Ji Q. Phospholipase C-gamma as a signal-transducing element. Exp Cell Res. 1999;253:15–24. [PubMed] [Google Scholar]

18. Spitaler M, Cantrell DA. Protein kinase C and beyond. Nat Immunol. 2004;5:785–790. [PubMed] [Google Scholar]

19. Griner EM, Kazanietz MG. Protein kinase C and other diacylglycerol effectors in cancer. Nat Rev Cancer. 2007;7:281–294. [PubMed] [Google Scholar]

20. Mackay HJ, Twelves CJ. Targeting the protein kinase C family: are we there yet? Nat Rev Cancer. 2007;7:554–562. [PubMed] [Google Scholar]

21. Marti U, Burwen SJ, Wells A, Barker ME, Huling S, Feren AM, et al. Localization of epidermal growth factor receptor in hepatocyte nuclei. Hepatology. 1991;13:15–20. [PubMed] [Google Scholar]

22. Cao H, Lei ZM, Bian L, Rao CV. Functional nuclear epidermal growth factor receptors in human choriocarcinoma JEG-3 cells and normal human placenta. Endocrinology. 1995;136:3163–3172. [PubMed] [Google Scholar]

23. Lin SY, Makino K, Xia W, Matin A, Wen Y, Kwong KY, et al. Nuclear localization of EGF receptor and its potential new role as a transcription factor. Nat Cell Biol. 2001;3:802–808. [PubMed] [Google Scholar]

24. Lo HW, Hsu SC, Hung MC. EGFR signaling pathway in breast cancers: from traditional signal transduction to direct nuclear translocalization. Breast Cancer Res Treat. 2006;95:211–218. [PubMed] [Google Scholar]

25. Lo HW, Hung MC. Nuclear EGFR signalling network in cancers: linking EGFR pathway to cell cycle progression, nitric oxide pathway and patient survival. Br J Cancer. 2006;94:184–188. [PMC free article] [PubMed] [Google Scholar]

26. Lo HW, Xia W, Wei Y, Ali-Seyed M, Huang SF, Hung MC. Novel prognostic value of nuclear epidermal growth factor receptor in breast cancer. Cancer Res. 2005;65:338–348. [PubMed] [Google Scholar]

27. Psyrri A, Yu Z, Weinberger PM, Sasaki C, Haffty B, Camp R, et al. Quantitative determination of nuclear and cytoplasmic epidermal growth factor receptor expression in oropharyngeal squamous cell cancer by using automated quantitative analysis. Clin Cancer Res. 2005;11:5856–5862. [PubMed] [Google Scholar]

28. Xia W, Wei Y, Du Y, Liu J, Chang B, Yu YL, et al. Nuclear expression of epidermal growth factor receptor is a novel prognostic value in patients with ovarian cancer. Mol Carcinog. 2009;48:610–617. [PMC free article] [PubMed] [Google Scholar]

29. Lo HW, Hsu SC, Ali-Seyed M, Gunduz M, Xia W, Wei Y, et al. Nuclear interaction of EGFR and STAT3 in the activation of the iNOS/NO pathway. Cancer Cell. 2005;7:575–589. [PubMed] [Google Scholar]

30. Hsu SC, Hung MC. Characterization of a novel tripartite nuclear localization sequence in the EGFR family. J Biol Chem. 2007;282:10432–10440. [PubMed] [Google Scholar]

31. Lo HW, Cao X, Zhu H, Ali-Osman F. Cyclooxygenase-2 is a novel transcriptional target of the nuclear EGFRSTAT3 and EGFRvIII-STAT3 signaling axes. Mol Cancer Res. 2010;8:232–245. [PMC free article] [PubMed] [Google Scholar]

32. Lo HW, Ali-Seyed M, Wu Y, Bartholomeusz G, Hsu SC, Hung MC. Nuclear-cytoplasmic transport of EGFR involves receptor endocytosis, importin beta1 and CRM1. J Cell Biochem. 2006;98:1570–1583. [PubMed] [Google Scholar]

33. Liao HJ, Carpenter G. Role of the Sec61 translocon in EGF receptor trafficking to the nucleus and gene expression. Mol Biol Cell. 2007;18:1064–1072. [PMC free article] [PubMed] [Google Scholar]

34. Hanada N, Lo HW, Day CP, Pan Y, Nakajima Y, Hung MC. Co-regulation of B-Myb expression by E2F1 and EGF receptor. Mol Carcinog. 2006;45:10–17. [PubMed] [Google Scholar]

35. Hung LY, Tseng JT, Lee YC, Xia W, Wang YN, Wu ML, et al. Nuclear epidermal growth factor receptor (EGFR) interacts with signal transducer and activator of transcription 5 (STAT5) in activating Aurora-A gene expression. Nucleic Acids Res. 2008;36:4337–4351. [PMC free article] [PubMed] [Google Scholar]

36. Wang SC, Nakajima Y, Yu YL, Xia W, Chen CT, Yang CC, et al. Tyrosine phosphorylation controls PCNA function through protein stability. Nat Cell Biol. 2006;8:1359–1368. [PubMed] [Google Scholar]

37. Dittmann K, Mayer C, Kehlbach R, Rodemann HP. Radiation-induced caveolin-1 associated EGFR internalization is linked with nuclear EGFR transport and activation of DNA-PK. Mol Cancer. 2008;7:69. [PMC free article] [PubMed] [Google Scholar]

38. Liao HJ, Carpenter G. Cetuximab/C225-induced intracellular trafficking of epidermal growth factor receptor. Cancer Res. 2009;69:6179–6183. [PMC free article] [PubMed] [Google Scholar]

39. Citri A, Yarden Y. EGF-ERBB signalling: towards the systems level. Nat Rev Mol Cell Bio. 2006;7:505–516. [PubMed] [Google Scholar]

40. Haglund K, Sigismund S, Polo S, Szymkiewicz I, Di Fiore PP, Dikic I. Multiple monoubiquitination of RTKs is sufficient for their endocytosis and degradation. Nat Cell Biol. 2003;5:461–466. [PubMed] [Google Scholar]

41. Mineo C, Gill GN, Anderson GW. Regulated migration of epidermal growth factor receptor from caveolae. J Biol Chem. 1999;274:30636–30643. [PubMed] [Google Scholar]

42. Vieira AV, Lamaze C, Schmid SL. Control of EGF receptor signaling by clathrin-mediated endocytosis. Science. 1996;274:2086–2089. [PubMed] [Google Scholar]

43. Yamabhai M, Anderson RGW. Second cysteine-rich region of epidermal growth factor receptor contains targeting information for caveolae/rafts. J Biol Chem. 2002;277:24843–24846. [PubMed] [Google Scholar]

44. Soubeyran P, Kowanetz K, Szymkiewicz I, Langdon WY, Dikic I. Cbl-CIN85-endophilin complex mediates ligand-induced downregulation of EGF receptors. Nature. 2002;416:183–187. [PubMed] [Google Scholar]

45. de Melker AA, van der Horst G, Borst J. c-Cbl directs EGF receptors into an endocytic pathway that involves the ubiquitin-interacting motif of Eps15. J Cell Sci. 2004;117:5001–5012. [PubMed] [Google Scholar]

46. Marmor MD, Yarden Y. Role of protein ubiquitylation in regulating endocytosis of receptor tyrosine kinases. Oncogene. 2004;23:2057–2070. [PubMed] [Google Scholar]

47. Bache KG, Slagsvold T, Stenmark H. Defective down-regulation of receptor tyrosine kinases in cancer. EMBO J. 2004;23:2707–2712. [PMC free article] [PubMed] [Google Scholar]

48. Hendriks BS, Opresko LK, Wiley HS, Lauffenburger D. Coregulation of epidermal growth factor receptor/human epidermal growth factor receptor 2 (HER2) levels and locations: Quantitative analysis of HER2 overexpression effects. Cancer Res. 2003;63:1130–1137. [PubMed] [Google Scholar]

49. Worthylake R, Opresko LK, Wiley HS. ErbB-2 amplification inhibits downregulation and induces constitutive activation of both ErbB-2 and epidermal growth factor receptors. J Biol Chem. 1999;274:8865–8874. [PubMed] [Google Scholar]

50. Baulida J, Kraus MH, Alimandi M, DiFiore PP, Carpenter G. All ErbB receptors other than the epidermal growth factor receptor are endocytosis impaired. J Biol Chem. 1996;271:5251–5257. [PubMed] [Google Scholar]

51. Sorkin A, Waters CM. Endocytosis of growth-factor receptors. Bioessays. 1993;15:375–382. [PubMed] [Google Scholar]

52. Wang ZX, Zhang LF, Yeung TK, Chen XM. Endocytosis deficiency of epidermal growth factor (EGF) receptor-ErbB2 heterodimers in response to EGF stimulation. Mol Biol Cell. 1999;10:1621–1636. [PMC free article] [PubMed] [Google Scholar]

53. Chung BM, Raja SM, Clubb RJ, Tu C, George M, Band V, et al. Aberrant trafficking of NSCLCassociated EGFR mutants through the endocytic recycling pathway promotes interaction with Src@. Bmc Cell Biol. 2009 In press. [PMC free article] [PubMed] [Google Scholar]

54. Hendriks BS, Wiley HS, Lauffenburger D. HER2-mediated effects on EGFR endosomal sorting: Analysis of biophysical mechanisms. Biophys J. 2003;85:2732–45. [PMC free article] [PubMed] [Google Scholar]

55. Weichselbaum RR, Dunphy EJ, Beckett MA, Tybor AG, Moran WJ, Goldman ME, et al. Epidermal growth factor receptor gene amplification and expression in head and neck cancer cell lines. Head Neck. 1989;11:437–442. [PubMed] [Google Scholar]

56. Veale D, Ashcroft T, Marsh C, Gibson GJ, Harris AL. Epidermal growth factor receptors in non-small cell lung cancer. Br J Cancer. 1987;55:513–516. [PMC free article] [PubMed] [Google Scholar]

57. Libermann TA, Razon N, Bartal AD, Yarden Y, Schlessinger J, Soreq H. Expression of epidermal growth factor receptors in human brain tumors. Cancer Res. 1984;44:753–760. [PubMed] [Google Scholar]

58. Libermann TA, Nusbaum HR, Razon N, Kris R, Lax I, Soreq H, et al. Amplification, enhanced expression and possible rearrangement of EGF receptor gene in primary human brain tumours of glial origin. Nature. 1985;313:144–147. [PubMed] [Google Scholar]

59. Libermann TA, Nusbaum HR, Razon N, Kris R, Lax I, Soreq H, et al. Amplification and overexpression of the EGF receptor gene in primary human glioblastomas. J Cell Sci Suppl. 1985;3:161–172. [PubMed] [Google Scholar]

60. Maurizi M, Almadori G, Ferrandina G, Distefano M, Romanini ME, Cadoni G, et al. Prognostic significance of epidermal growth factor receptor in laryngeal squamous cell carcinoma. Br J Cancer. 1996;74:1253–1257. [PMC free article] [PubMed] [Google Scholar]

61. FischerColbrie J, Witt A, Heinzl H, Speiser P, Czerwenka K, Sevelda P, et al. EGFR and steroid receptors in ovarian carcinoma: Comparison with prognostic parameters and outcome of patients. Anticancer Res. 1997;17:613–619. [PubMed] [Google Scholar]

62. Kersemaekers AMF, Fleuren GJ, Kenter EG, Van den Broek LJCM, Uljee SM, Hermans J, et al. Oncogene alterations in carcinomas of the uterine cervix: Overexpression of the epidermal growth factor receptor is associated with poor prognosis. Clin Cancer Res. 1999;5:577–586. [PubMed] [Google Scholar]

63. Mellon K, Wright C, Kelly P, Horne CHW, Neal DE. Long-term outcome related to epidermal growth-factor receptor status in bladder-cancer. Journal of Urology. 1995;153:919–925. [PubMed] [Google Scholar]

64. Inada S, Koto T, Futami K, Arima S, Iwashita A. Evaluation of malignancy and the prognosis of esophageal cancer based on an immunohistochemical study (p53, E-cadherin, epidermal growth factor receptor) Surg Today. 1999;29:493–503. [PubMed] [Google Scholar]

65. Ohgaki H, Watanabe K, Tachibana O, Sato K, Kleihues P. Overexpression of the EGF receptor and p53 mutations are mutually exclusive in the evolution of primary and secondary glioblastomas. J Neuropathol Exp Neurol. 1996;55:3. [PubMed] [Google Scholar]

66. Nicholson RI, Gee JM, Harper ME. EGFR and cancer prognosis. Eur J Cancer. 2001;37:9–15. [PubMed] [Google Scholar]

67. Nielsen JS, Jakobsen E, Holund B, Bertelsen K, Jakobsen A. Prognostic significance of p53, Her-2 and EGFR overexpression in borderline and epithelial ovarian cancer. Int J Gynecol Cancer. 2004;14:1086–1096. [PubMed] [Google Scholar]

68. Santini J, Formento JL, Francoual M, Milano G, Schneider M, Dassonville O, et al. Characterization, quantification and potential clinical-value of the epidermal growth-factor receptor in head and neck squamous-cell carcinomas. Head Neck. 1991;13:132–139. [PubMed] [Google Scholar]

69. Yasui W, Sumiyoshi H, Hata J, Kameda T, Ochiai A, Ito H, et al. Expression of epidermal growth-factor receptor in human gastric and colonic carcinomas. Cancer Res. 1988;48:137–141. [PubMed] [Google Scholar]

70. Piyathilake CJ, Frost AR, Manne U, Weiss H, Bell WC, Heimburger DC, et al. Differential expression of growth factors in squamous cell carcinoma and pre-cancerous lesions of the lung. Clin Cancer Res. 2002;8:734–744. [PubMed] [Google Scholar]

71. Scambia G, Panici PB, Ferrandina G, Battaglia F, Distefano M, Dandrea G, et al. Significance of epidermal growth-factor receptor expression in primary human endometrial cancer. Int J Cancer. 1994;56:26–30. [PubMed] [Google Scholar]

72. Nicholson RI, Gee JMW, Harper ME. EGFR and cancer prognosis. Eur J Cancer. 2001;37:9–15. [PubMed] [Google Scholar]

73. Sizeland AM, Burgess AW. Anti-sense transforming growth factor alpha oligonucleotides inhibit autocrine stimulated proliferation of a colon carcinoma cell line. Mol Biol Cell. 1992;3:1235–1243. [PMC free article] [PubMed] [Google Scholar]

74. Humphrey PA, Wong AJ, Vogelstein B, Zalutsky MR, Fuller GN, Archer GE, et al. Anti-synthetic peptide antibody reacting at the fusion junction of deletion-mutant epidermal growth factor receptors in human glioblastoma. Proc Natl Acad Sci USA. 1990;87:4207–4211. [PMC free article] [PubMed] [Google Scholar]

75. Malden LT, Novak U, Kaye AH, Burgess AW. Selective amplification of the cytoplasmic domain of the epidermal growth factor receptor gene in glioblastoma multiforme. Cancer Res. 1988;48:2711–2714. [PubMed] [Google Scholar]

76. Peschard P, Park M. Escape from Cbl-mediated down-regulation: a recurrent theme for oncogenic deregulation of receptor tyrosine kinases. Cancer Cell. 2003;3:519–523. [PubMed] [Google Scholar]

77. Gill GN, Kawamoto T, Cochet C, Le A, Sato JD, Masui H, et al. Monoclonal anti-epidermal growth factor receptor antibodies which are inhibitors of epidermal growth factor binding and antagonists of epidermal growth factor-stimulated tyrosine protein kinase activity. J Biol Chem. 1984;259:7755–7760. [PubMed] [Google Scholar]

78. Kawamoto T, Sato JD, Le A, Polikoff J, Sato GH, Mendelsohn J. Growth stimulation of A431 cells by epidermal growth factor: identification of high-affinity receptors for epidermal growth factor by an anti-receptor monoclonal antibody. Proc Natl Acad Sci USA. 1983;80:1337–1341. [PMC free article] [PubMed] [Google Scholar]

79. Sato JD, Kawamoto T, Le AD, Mendelsohn J, Polikoff J, Sato GH. Biological effects in vitro of monoclonal antibodies to human epidermal growth factor receptors. Mol Biol Med. 1983;1:511–529. [PubMed] [Google Scholar]

80. Masui H, Kawamoto T, Sato JD, Wolf B, Sato G, Mendelsohn J. Growth inhibition of human tumor cells in athymic mice by anti-epidermal growth factor receptor monoclonal antibodies. Cancer Res. 1984;44:1002–1007. [PubMed] [Google Scholar]

81. Li S, Schmitz KR, Jeffrey PD, Wiltzius JJ, Kussie P, Ferguson KM. Structural basis for inhibition of the epidermal growth factor receptor by cetuximab. Cancer Cell. 2005;7:301–311. [PubMed] [Google Scholar]

82. Yang XD, Jia XC, Corvalan JRF, Wang P, Davis CG. Development of ABX-EGF, a fully human anti-EGF receptor monoclonal antibody, for cancer therapy. Crit Rev Oncol Hemat. 2001;38:17–23. [PubMed] [Google Scholar]

83. Sunada H, Magun BE, Mendelsohn J, MacLeod CL. Monoclonal antibody against epidermal growth factor receptor is internalized without stimulating receptor phosphorylation. Proc Natl Acad Sci USA. 1986;83:3825–3829. [PMC free article] [PubMed] [Google Scholar]

84. Goldstein NI, Prewett M, Zuklys K, Rockwell P, Mendelsohn J. Biological efficacy of a chimeric antibody to the epidermal growth factor receptor in a human tumor xenograft model. Clin Cancer Res. 1995;1:1311–1318. [PubMed] [Google Scholar]

85. Sunada H, Magun BE, Mendelsohn J, Macleod CL. Monoclonal-antibody against epidermal growth-factor receptor is internalized without stimulating receptor phosphorylation. Proc Natl Acad Sci USA. 1986;83:3825–3829. [PMC free article] [PubMed] [Google Scholar]

86. Huang SM, Bock JM, Harari PM. Epidermal growth factor receptor blockade with C225 modulates proliferation, apoptosis and radiosensitivity in squamous cell carcinomas of the head and neck. Cancer Res. 1999;59:1935–1940. [PubMed] [Google Scholar]

87. Peng D, Fan Z, Lu Y, DeBlasio T, Scher H, Mendelsohn J. Anti-epidermal growth factor receptor monoclonal antibody 225 upregulates p27KIP1 and induces G1 arrest in prostatic cancer cell line DU145. Cancer Res. 1996;56:3666–3669. [PubMed] [Google Scholar]

88. Wu X, Rubin M, Fan Z, DeBlasio T, Soos T, Koff A, et al. Involvement of p27KIP1 in G1 arrest mediated by an anti-epidermal growth factor receptor monoclonal antibody. Oncogene. 1996;12:1397–403. [PubMed] [Google Scholar]

89. Baselga J. The EGFR as a target for anticancer therapy—focus on cetuximab. Eur J Cancer. 2001;37:16–22. [PubMed] [Google Scholar]

90. P OC, Rhys-Evans P, Modjtahedi H, Court W, Box G, Eccles S. Overexpression of epidermal growth factor receptor in human head and neck squamous carcinoma cell lines correlates with matrix metalloproteinase-9 expression and in vitro invasion. Int J Cancer. 2000;86:307–317. [PubMed] [Google Scholar]

91. P Oc, Rhys-Evans P, Court WJ, Box GM, Eccles SA. Differential modulation of proliferation, matrix metalloproteinase expression and invasion of human head and neck squamous carcinoma cells by c-erbB ligands. Clin Exp Metastasis. 1999;17:631–639. [PubMed] [Google Scholar]

92. Bruns CJ, Harbison MT, Davis DW, Portera CA, Tsan R, McConkey DJ, et al. Epidermal growth factor receptor blockade with C225 plus gemcitabine results in regression of human pancreatic carcinoma growing orthotopically in nude mice by antiangiogenic mechanisms. Clin Cancer Res. 2000;6:1936–1948. [PubMed] [Google Scholar]

93. Perrotte P, Matsumoto T, Inoue K, Kuniyasu H, Eve BY, Hicklin DJ, et al. Anti-epidermal growth factor receptor antibody C225 inhibits angiogenesis in human transitional cell carcinoma growing orthotopically in nude mice. Clin Cancer Res. 1999;5:257–265. [PubMed] [Google Scholar]

94. Tortora G, Caputo R, Pomatico G, Pepe S, Bianco AR, Agrawal S, et al. Cooperative inhibitory effect of novel mixed backbone oligonucleotide targeting protein kinase A in combination with docetaxel and anti-epidermal growth factor-receptor antibody on human breast cancer cell growth. Clin Cancer Res. 1999;5:875–881. [PubMed] [Google Scholar]

95. Liu B, Fang M, Schmidt M, Lu Y, Mendelsohn J, Fan Z. Induction of apoptosis and activation of the caspase cascade by anti-EGF receptor monoclonal antibodies in DiFi human colon cancer cells do not involve the c-jun N-terminal kinase activity. Br J Cancer. 2000;82:1991–1999. [PMC free article] [PubMed] [Google Scholar]

96. Mandal M, Adam L, Mendelsohn J, Kumar R. Nuclear targeting of Bax during apoptosis in human colorectal cancer cells. Oncogene. 1998;17:999–1007. [PubMed] [Google Scholar]

97. Wu X, Fan Z, Masui H, Rosen N, Mendelsohn J. Apoptosis induced by an anti-epidermal growth factor receptor monoclonal antibody in a human colorectal carcinoma cell line and its delay by insulin. J Clin Invest. 1995;95:1897–1905. [PMC free article] [PubMed] [Google Scholar]

98. Kurai J, Chikumi H, Hashimoto K, Yamaguchi K, Yamasaki A, Sako T, et al. Antibody-dependent cellular cytotoxicity mediated by cetuximab against lung cancer cell lines. Clin Cancer Res. 2007;13:1552–1561. [PubMed] [Google Scholar]

99. Kimura H, Sakai K, Arao T, Shimoyama T, Tamura T, Nishio K. Antibody-dependent cellular cytotoxicity of cetuximab against tumor cells with wild-type or mutant epidermal growth factor receptor. Cancer Sci. 2007;98:1275–1280. [PMC free article] [PubMed] [Google Scholar]

100. Chung KY, Shia J, Kemeny NE, Shah M, Schwartz GK, Tse A, et al. Cetuximab shows activity in colorectal cancer patients with tumors that do not express the epidermal growth factor receptor by immunohistochemistry. J Clin Oncol. 2005;23:1803–1810. [PubMed] [Google Scholar]

101. Jonker DJ, O'Callaghan CJ, Karapetis CS, Zalcberg JR, Tu D, Au HJ, et al. Cetuximab for the treatment of colorectal cancer. N Engl J Med. 2007;357:2040–2048. [PubMed] [Google Scholar]

102. Sobrero AF, Maurel J, Fehrenbacher L, Scheithauer W, Abubakr YA, Lutz MP, et al. EPIC: phase III trial of cetuximab plus irinotecan after fluoropyrimidine and oxaliplatin failure in patients with metastatic colorectal cancer. J Clin Oncol. 2008;26:2311–2319. [PubMed] [Google Scholar]

103. Borner M, Koeberle D, Von Moos R, Saletti P, Rauch D, Hess V, et al. Adding cetuximab to capecitabine plus oxaliplatin (XELOX) in first-line treatment of metastatic colorectal cancer: a randomized phase II trial of the Swiss Group for Clinical Cancer Research SAKK. Ann Oncol. 2008;19:1288–1292. [PubMed] [Google Scholar]

104. Bokemeyer C, Bondarenko I, Makhson A, Hartmann JT, Aparicio J, de Braud F, et al. Fluorouracil, leucovorin and oxaliplatin with and without cetuximab in the first-line treatment of metastatic colorectal cancer. J Clin Oncol. 2009;27:663–671. [PubMed] [Google Scholar]

105. Van Cutsem E, Kohne CH, Hitre E, Zaluski J, Chang Chien CR, Makhson A, et al. Cetuximab and chemotherapy as initial treatment for metastatic colorectal cancer. N Engl J Med. 2009;360:1408–1417. [PubMed] [Google Scholar]

106. Vermorken JB, Mesia R, Rivera F, Remenar E, Kawecki A, Rottey S, et al. Platinum-based chemotherapy plus cetuximab in head and neck cancer. N Engl J Med. 2008;359:1116–1127. [PubMed] [Google Scholar]

107. Bonner JA, Harari PM, Giralt J, Azarnia N, Shin DM, Cohen RB, et al. Radiotherapy plus cetuximab for squamous-cell carcinoma of the head and neck. N Engl J Med. 2006;354:567–578. [PubMed] [Google Scholar]

108. Herbst RS, Arquette M, Shin DM, Dicke K, Vokes EE, Azarnia N, et al. Phase II multicenter study of the epidermal growth factor receptor antibody cetuximab and cisplatin for recurrent and refractory squamous cell carcinoma of the head and neck. J Clin Oncol. 2005;23:5578–5587. [PubMed] [Google Scholar]

109. Baselga J, Trigo JM, Bourhis J, Tortochaux J, Cortes-Funes H, Hitt R, et al. Phase II multicenter study of the antiepidermal growth factor receptor monoclonal antibody cetuximab in combination with platinum-based chemotherapy in patients with platinum-refractory metastatic and/or recurrent squamous cell carcinoma of the head and neck. J Clin Oncol. 2005;23:5568–5577. [PubMed] [Google Scholar]

110. Burtness B, Goldwasser MA, Flood W, Mattar B, Forastiere AA. Phase III randomized trial of cisplatin plus placebo compared with cisplatin plus cetuximab in metastatic/recurrent head and neck cancer: an eastern Cooperative Oncology Group study. J Clin Oncol. 2005;23:8646–8654. [PubMed] [Google Scholar]

111. Cunningham D, Humblet Y, Siena S, Khayat D, Bleiberg H, Santoro A, et al. Cetuximab monotherapy and cetuximab plus irinotecan in irinotecan-refractory metastatic colorectal cancer. N Engl J Med. 2004;351:337–345. [PubMed] [Google Scholar]

112. Robert F, Ezekiel MP, Spencer SA, Meredith RF, Bonner JA, Khazaeli MB, et al. Phase I study of antiepidermal growth factor receptor antibody cetuximab in combination with radiation therapy in patients with advanced head and neck cancer. J Clin Oncol. 2001;19:3234–3243. [PubMed] [Google Scholar]

113. Thienelt CD, Bunn PA Jr, Hanna N, Rosenberg A, Needle MN, Long ME, et al. Multicenter phase I/II study of cetuximab with paclitaxel and carboplatin in untreated patients with stage IV non-small-cell lung cancer. J Clin Oncol. 2005;23:8786–8793. [PubMed] [Google Scholar]

114. Rosell R, Robinet G, Szczesna A, Ramlau R, Constenla M, Mennecier BC, et al. Randomized phase II study of cetuximab plus cisplatin/vinorelbine compared with cisplatin/vinorelbine alone as first-line therapy in EGFR-expressing advanced non-small-cell lung cancer. Ann Oncol. 2008;19:362–369. [PubMed] [Google Scholar]

115. Robert F, Blumenschein G, Herbst RS, Fossella FV, Tseng J, Saleh MN, et al. Phase I/IIa study of cetuximab with gemcitabine plus carboplatin in patients with chemotherapy-naive advanced non-small-cell lung cancer. J Clin Oncol. 2005;23:9089–9096. [PubMed] [Google Scholar]

116. Herbst RS, Chansky K, Kelly K, Atkins JN, Davies AM, Dakhil SR, et al. phase II randomized selection trial evaluating concurrent chemotherapy plus cetuximab or chemotherapy followed by cetuximab in patients with advanced non-small cell lung cancer (NSCLC): Final report of SWOG 0342. ASCO; 2007. [Google Scholar]

117. Butts CA, Bodkin D, Middleman EL, Englund CW, Ellison D, Alam Y, et al. Randomized phase II study of gemcitabine plus cisplatin or carboplatin [corrected], with or without cetuximab, as first-line therapy for patients with advanced or metastatic non small-cell lung cancer. J Clin Oncol. 2007;25:5777–5784. [PubMed] [Google Scholar]

118. Pirker R, Pereira JR, Szczesna A, von Pawel J, Krzakowski M, Ramlau R, et al. Cetuximab plus chemotherapy in patients with advanced non-small-cell lung cancer (FLEX): an open-label randomised phase III trial. Lancet. 2009;373:1525–1531. [PubMed] [Google Scholar]

119. Lynch TJ, Patel T, Dreisbach L, McCleod M, Heim WJ, Hermann RC, et al. Cetuximab and first-line taxane/carboplatin chemotherapy in advanced non-small-cell lung cancer: results of the randomized multicenter phase III trial BMS099. J Clin Oncol. 2010;28:911–917. [PubMed] [Google Scholar]

120. Pao W, Miller V, Zakowski M, Doherty J, Politi K, Sarkaria I, et al. EGF receptor gene mutations are common in lung cancers from “never smokers” and are associated with sensitivity of tumors to gefitinib and erlotinib. Proc Natl Acad Sci USA. 2004;101:13306–13311. [PMC free article] [PubMed] [Google Scholar]

121. Lynch TJ, Bell DW, Sordella R, Gurubhagavatula S, Okimoto RA, Brannigan BW, et al. Activating mutations in the epidermal growth factor receptor underlying responsiveness of non-small-cell lung cancer to gefitinib. N Engl J Med. 2004;350:2129–2139. [PubMed] [Google Scholar]

122. Paez JG, Janne PA, Lee JC, Tracy S, Greulich H, Gabriel S, et al. EGFR mutations in lung cancer: correlation with clinical response to gefitinib therapy. Science. 2004;304:1497–1500. [PubMed] [Google Scholar]

123. Pao W, Miller VA, Politi KA, Riely GJ, Somwar R, Zakowski MF, et al. Acquired resistance of lung adenocarcinomas to gefitinib or erlotinib is associated with a second mutation in the EGFR kinase domain. PLoS Med. 2005;2:73. [PMC free article] [PubMed] [Google Scholar]

124. Kobayashi S, Boggon TJ, Dayaram T, Janne PA, Kocher O, Meyerson M, et al. EGFR mutation and resistance of non-small-cell lung cancer to gefitinib. N Engl J Med. 2005;352:786–792. [PubMed] [Google Scholar]

125. Tsuchihashi Z, Khambata-Ford S, Hanna N, Janne PA. Responsiveness to cetuximab without mutations in EGFR. N Engl J Med. 2005;353:208–209. [PubMed] [Google Scholar]

126. Mukohara T, Engelman JA, Hanna NH, Yeap BY, Kobayashi S, Lindeman N, et al. Differential effects of gefitinib and cetuximab on non-small-cell lung cancers bearing epidermal growth factor receptor mutations. J Natl Cancer Inst. 2005;97:1185–1194. [PubMed] [Google Scholar]

127. Moroni M, Veronese S, Benvenuti S, Marrapese G, Sartore-Bianchi A, Di Nicolantonio F, et al. Gene copy number for epidermal growth factor receptor (EGFR) and clinical response to antiEGFR treatment in colorectal cancer: a cohort study. Lancet Oncol. 2005;6:279–286. [PubMed] [Google Scholar]

128. Frattini M, Saletti P, Romagnani E, Martin V, Molinari F, Ghisletta M, et al. PTEN loss of expression predicts cetuximab efficacy in metastatic colorectal cancer patients. Br J Cancer. 2007;97:1139–1145. [PMC free article] [PubMed] [Google Scholar]

129. Personeni N, Fieuws S, Piessevaux H, De Hertogh G, De Schutter J, Biesmans B, et al. Clinical usefulness of EGFR gene copy number as a predictive marker in colorectal cancer patients treated with cetuximab: a fluorescent in situ hybridization study. Clin Cancer Res. 2008;14:5869–5876. [PubMed] [Google Scholar]

130. Cappuzzo F, Finocchiaro G, Rossi E, Janne PA, Carnaghi C, Calandri C, et al. EGFR FISH assay predicts for response to cetuximab in chemotherapy refractory colorectal cancer patients. Ann Oncol. 2008;19:717–723. [PubMed] [Google Scholar]

131. Sartore-Bianchi A, Moroni M, Veronese S, Carnaghi C, Bajetta E, Luppi G, et al. Epidermal growth factor receptor gene copy number and clinical outcome of metastatic colorectal cancer treated with panitumumab. J Clin Oncol. 2007;25:3238–3245. [PubMed] [Google Scholar]

132. Hirsch FR, Herbst RS, Olsen C, Chansky K, Crowley J, Kelly K, et al. Increased EGFR gene copy number detected by fluorescent in situ hybridization predicts outcome in non-small-cell lung cancer patients treated with cetuximab and chemotherapy. J Clin Oncol. 2008;26:3351–3357. [PMC free article] [PubMed] [Google Scholar]

133. Khambata-Ford S, Harbison CT, Hart LL, Awad M, Xu LA, Horak CE, et al. Analysis of potential predictive markers of cetuximab benefit in BMS099, a phase III study of cetuximab and first-line taxane/carboplatin in advanced non-small-cell lung cancer. J Clin Oncol. 2010;28:918–927. [PubMed] [Google Scholar]

134. Khambata-Ford S, Garrett CR, Meropol NJ, Basik M, Harbison CT, Wu S, et al. Expression of epiregulin and amphiregulin and K-ras mutation status predict disease control in metastatic colorectal cancer patients treated with cetuximab. J Clin Oncol. 2007;25:3230–3237. [PubMed] [Google Scholar]

135. Trahey M, McCormick F. A cytoplasmic protein stimulates normal N-ras p21 GTPase, but does not affect oncogenic mutants. Science. 1987;238:542–545. [PubMed] [Google Scholar]

136. Schubbert S, Shannon K, Bollag G. Hyperactive Ras in developmental disorders and cancer. Nat Rev Cancer. 2007;7:295–308. [PubMed] [Google Scholar]

137. Lievre A, Bachet JB, Le Corre D, Boige V, Landi B, Emile JF, et al. KRAS mutation status is predictive of response to cetuximab therapy in colorectal cancer. Cancer Res. 2006;66:3992–3995. [PubMed] [Google Scholar]

138. Di Fiore F, Blanchard F, Charbonnier F, Le Pessot F, Lamy A, Galais MP, et al. Clinical relevance of KRAS mutation detection in metastatic colorectal cancer treated by Cetuximab plus chemotherapy. Br J Cancer. 2007;96:1166–1169. [PMC free article] [PubMed] [Google Scholar]

139. De Roock W, Piessevaux H, De Schutter J, Janssens M, De Hertogh G, Personeni N, et al. KRAS wild-type state predicts survival and is associated to early radiological response in metastatic colorectal cancer treated with cetuximab. Ann Oncol. 2008;19:508–515. [PubMed] [Google Scholar]

140. Punt CJ, Tol J, Rodenburg CJ, Cats A, Creemers GM, Schrama JG, et al. Randomized phase III study of capecitabine, oxaliplatin and bevacizumab with or without cetuximab in advanced colorectal cancer (ACC), the CAIRO2 study of the Dutch Colorectal Cancer Group (DCCG); ASCO Meeting Abstracts; May 20 2008.2008. [PubMed] [Google Scholar]

141. Van Cutsem E, Lang I, D'haens G, Moiseyenko V, Zaluski J, Folprecht G, et al. KRAS status and efficacy in the first-line treatment of patients with metastatic colorectal cancer (mCRC) treated with FOLFIRI with or without cetuximab: The CRYSTAL experience. ASCO Meeting Abstracts. 2008;2:2008. [Google Scholar]

142. Bokemeyer C, Bondarenko I, Hartmann J, De Braud F, Volovat C, Nippgen L, et al. KRAS status and efficacy of first-line treatment of patients with metastatic colorectal cancer (mCRC) with FOLFOX with or without cetuximab: The OPUS experience. ASCO Meeting Abstracts. 2008:4000. [Google Scholar]

143. Karapetis CS, Khambata-Ford S, Jonker DJ, O'Callaghan CJ, Tu D, Tebbutt NC, et al. K-ras mutations and benefit from cetuximab in advanced colorectal cancer. N Engl J Med. 2008;359:1757–1765. [PubMed] [Google Scholar]

144. Amado RG, Wolf M, Peeters M, Van Cutsem E, Siena S, Freeman DJ, et al. Wild-type KRAS is required for panitumumab efficacy in patients with metastatic colorectal cancer. J Clin Oncol. 2008;26:1626–1634. [PubMed] [Google Scholar]

145. Allegra CJ, Jessup JM, Somerfield MR, Hamilton SR, Hammond EH, Hayes DF, et al. American Society of Clinical Oncology provisional clinical opinion: testing for KRAS gene mutations in patients with metastatic colorectal carcinoma to predict response to anti-epidermal growth factor receptor monoclonal antibody therapy. J Clin Oncol. 2009;27:2091–2096. [PubMed] [Google Scholar]

146. Loupakis F, Pollina L, Stasi I, Ruzzo A, Scartozzi M, Santini D, et al. PTEN expression and KRAS mutations on primary tumors and metastases in the prediction of benefit from cetuximab plus irinotecan for patients with metastatic colorectal cancer. J Clin Oncol. 2009;27:2622–2629. [PubMed] [Google Scholar]

147. Benvenuti S, Sartore-Bianchi A, Di Nicolantonio F, Zanon C, Moroni M, Veronese S, et al. Oncogenic activation of the RAS/RAF signaling pathway impairs the response of metastatic colorectal cancers to antiepidermal growth factor receptor antibody therapies. Cancer Res. 2007;67:2643–2648. [PubMed] [Google Scholar]

148. Marais R, Light Y, Paterson HF, Marshall CJ. Ras recruits Raf-1 to the plasma membrane for activation by tyrosine phosphorylation. EMBO J. 1995;14:3136–3145. [PMC free article] [PubMed] [Google Scholar]

149. Roberts PJ, Der CJ. Targeting the Raf-MEK-ERK mitogen-activated protein kinase cascade for the treatment of cancer. Oncogene. 2007;26:3291–3310. [PubMed] [Google Scholar]

150. Niault TS, Baccarini M. Targets of Raf in tumorigenesis. Carcinogenesis. 2010;31:1165–1174. [PubMed] [Google Scholar]

151. Di Nicolantonio F, Martini M, Molinari F, Sartore-Bianchi A, Arena S, Saletti P, et al. Wild-type BRAF is required for response to panitumumab or cetuximab in metastatic colorectal cancer. J Clin Oncol. 2008;26:5705–5712. [PubMed] [Google Scholar]

152. Blanco R, Iwakawa R, Tang M, Kohno T, Angulo B, Pio R, et al. A gene-alteration profile of human lung cancer cell lines. Hum Mutat. 2009;30:1199–1206. [PMC free article] [PubMed] [Google Scholar]

153. Pratilas CA, Taylor BS, Ye Q, Viale A, Sander C, Solit DB, et al. (V600E)BRAF is associated with disabled feedback inhibition of RAF-MEK signaling and elevated transcriptional output of the pathway. Proc Natl Acad Sci USA. 2009;106:4519–4524. [PMC free article] [PubMed] [Google Scholar]

154. Brose MS, Volpe P, Feldman M, Kumar M, Rishi I, Gerrero R, et al. BRAF and RAS mutations in human lung cancer and melanoma. Cancer Res. 2002;62:6997–7000. [PubMed] [Google Scholar]

155. Davies H, Bignell GR, Cox C, Stephens P, Edkins S, Clegg S, et al. Mutations of the BRAF gene in human cancer. Nature. 2002;417:949–954. [PubMed] [Google Scholar]

156. Weber A, Langhanki L, Sommerer F, Markwarth A, Wittekind C, Tannapfel A. Mutations of the BRAF gene in squamous cell carcinoma of the head and neck. Oncogene. 2003;22:4757–4759. [PubMed] [Google Scholar]

157. Perrone F, Suardi S, Pastore E, Casieri P, Orsenigo M, Caramuta S, et al. Molecular and cytogenetic subgroups of oropharyngeal squamous cell carcinoma. Clin Cancer Res. 2006;12:6643–6651. [PubMed] [Google Scholar]

158. Fei Huang LAX, Khambata-Ford Shirin. Analysis of the correlation between gene expression of IGF-pathway components and benefit from cetuximab (Erbitux™) in metastatic colorectal cancer patients. AACR meeting Abstracts. 2010 [Google Scholar]

159. Perrotte P, Matsumoto T, Inoue K, Kuniyasu H, Eve BY, Hicklin DJ, et al. Anti-epidermal growth factor receptor antibody C225 inhibits angiogenesis in human transitional cell carcinoma growing orthotopically in nude mice. Clin Cancer Res. 1999;5:257–265. [PubMed] [Google Scholar]

160. Petit AMV, Rak J, Hung MC, Rockwell P, Goldstein N, Fendly B, et al. Neutralizing antibodies against epidermal growth factor and ErbB-2/neu receptor tyrosine kinases downregulate vascular endothelial growth factor production by tumor cells in vitro and in vivo—Angiogenic implications for signal transduction therapy of solid tumors. Am J Pathol. 1997;151:1523–1530. [PMC free article] [PubMed] [Google Scholar]

161. Ciardiello F, Bianco R, Damiano V, Fontanini G, Caputo R, Pomatico G, et al. Antiangiogenic and antitumor activity of anti-epidermal growth factor receptor C225 monoclonal antibody in combination with vascular endothelial growth factor antisense oligonucleotide in human GEO colon cancer cells. Clin Cancer Res. 2000;6:3739–3747. [PubMed] [Google Scholar]

162. Viloria-Petit A, Crombet T, Jothy S, Hicklin D, Bohlen P, Schlaeppi JM, et al. Acquired resistance to the antitumor effect of epidermal growth factor receptor-blocking antibodies in vivo: A role for altered tumor angiogenesis. Cancer Res. 2001;61:5090–5101. [PubMed] [Google Scholar]

163. Ferrara N. The role of vascular endothelial growth factor in pathological angiogenesis. Breast Cancer Res Treat. 1995;36:127–137. [PubMed] [Google Scholar]

164. Fontanini G, Vignati S, Boldrini L, Chine S, Silvestri V, Lucchi M, et al. Vascular endothelial growth factor is associated with neovascularization and influences progression of non-small cell lung carcinoma. Clin Cancer Res. 1997;3:861–865. [PubMed] [Google Scholar]

165. Jung YD, Mansfield PF, Akagi M, Takeda A, Liu W, Bucana CD, et al. Effects of combination anti-vascular endothelial growth factor receptor and anti-epidermal growth factor receptor therapies on the growth of gastric cancer in a nude mouse model. Eur J Cancer. 2002;38:1133–1140. [PubMed] [Google Scholar]

166. Ciardiello F, Bianco R, Caputo R, Caputo R, Damiano V, Troiani T, et al. Antitumor activity of ZD6474, a vascular endothelial growth factor receptor tyrosine kinase inhibitor, in human cancer cells with acquired resistance to antiepidermal growth factor receptor therapy. Clin Cancer Res. 2004;10:784–793. [PubMed] [Google Scholar]

167. Bianco R, Rosa R, Damiano V, Daniele G, Gelardi T, Garofalo S, et al. Vascular endothelial growth factor receptor-1 contributes to resistance to anti-epidermal growth factor receptor drugs in human cancer cells. Clin Cancer Res. 2008;14:5069–5080. [PubMed] [Google Scholar]

168. Lu Y, Li XQ, Liang K, Luwor R, Siddik ZH, Nuiis GB, et al. Epidermal growth factor receptor (EGFR) ubiquitination as a mechanism of acquired resistance escaping treatment by the Anti-EGFR monoclonal antibody cetuximab. Cancer Res. 2007;67:8240–8247. [PubMed] [Google Scholar]

169. Bao J, Gur G, Yarden Y. Src promotes destruction of c-Cbl: Implications for oncogenic synergy between Src and growth factor receptors. Proc Natl Acad Sci USA. 2003;100:2438–2443. [PMC free article] [PubMed] [Google Scholar]

170. Wheeler DL, Huang S, Kruser TJ, Nechrebecki MM, Armstrong EA, Benavente S, et al. Mechanisms of acquired resistance to cetuximab: role of HER (ErbB) family members. Oncogene. 2008;27:3944–3956. [PMC free article] [PubMed] [Google Scholar]

171. Grovdal LM, Stang E, Sorkin A, Madshus IH. Direct interaction of Cbl with pTyr 1045 of the EGF receptor (EGFR) is required to sort the EGFR to lysosomes for degradation. Exp Cell Res. 2004;300:388–395. [PubMed] [Google Scholar]

172. Demory ML, Boerner JL, Davidson R, Faust W, Miyake T, Lee I, et al. Epidermal growth factor receptor translocation to the mitochondria: regulation and effect. J Biol Chem. 2009;284:36592–36604. [PMC free article] [PubMed] [Google Scholar]

173. Lo HW, Cao X, Zhu H, Ali-Osman F. Constitutively Activated STAT3 Frequently Coexpresses with Epidermal Growth Factor Receptor in High-Grade Gliomas and Targeting STAT3 Sensitizes Them to Iressa and Alkylators. Clin Cancer Res. 2008;14:6042–6054. [PMC free article] [PubMed] [Google Scholar]

174. Lo HW, Hsu SC, Hung MC. EGFR signaling pathway in breast cancers: from traditional signal transduction to direct nuclear translocalization. Breast Cancer Res Tr. 2006;95:211–218. [PubMed] [Google Scholar]

175. Lo HW, Hsu SC, Ali-Seyed M, Gunduz M, Xia WY, Wei YK, et al. Nuclear interaction of EGFR and STAT3 in the activation of the iNOS/NO pathway. Cancer Cell. 2005;7:575–589. [PubMed] [Google Scholar]

176. Lo HW, Ali-Seyed M, Wu Y, Bartholomeusz G, Hsu SC, Hung MC. Nuclear-cytoplasmic transport of EGFR involves receptor endocytosis, importin beta1 and CRM1. J Cell Biochem. 2006;98:1570–1583. [PubMed] [Google Scholar]

177. Hanada N, Lo HW, Day CP, Pan Y, Nakajima Y, Hung MC. Co-regulation of B-Myb expression by E2F1 and EGF receptor. Mol Carcinogen. 2006;45:10–17. [PubMed] [Google Scholar]

178. Kim J, Jahng WJ, Di Vizio D, Lee JS, Jhaveri R, Rubin MA, et al. The phosphoinositide kinase PIKfyve mediates epidermal growth factor receptor trafficking to the nucleus. Cancer Res. 2007;67:9229–37. [PMC free article] [PubMed] [Google Scholar]

179. Xia WY, Wei YK, Du Y, Liu JS, Chang B, Yu YL, et al. Nuclear expression of epidermal growth factor receptor is a novel prognostic value in patients with ovarian cancer. Mol Carcinogen. 2009;48:610–617. [PMC free article] [PubMed] [Google Scholar]

180. Li C, Iida M, Dunn EF, Ghia AJ, Wheeler DL. Nuclear EGFR contributes to acquired resistance to cetuximab. Oncogene. 2009;28:3801–3813. [PMC free article] [PubMed] [Google Scholar]

181. Lin SY, Makino K, Xia WY, Matin A, Wen Y, Kwong KY, et al. Nuclear localization of EGF receptor and its potential new role as a transcription factor. Nat Cell Biol. 2001;3:802–808. [PubMed] [Google Scholar]

182. Li C, Iida M, Dunn EF, Ghia AJ, Wheeler DL. Nuclear EGFR contributes to acquired resistance to cetuximab. Oncogene. 2009;28:3801–3813. [PMC free article] [PubMed] [Google Scholar]

183. Bandyopadhyay D, Mandal M, Adam L, Mendelsohn J, Kumar R. Physical interaction between epidermal growth factor receptor and DNA-dependent protein kinase in mammalian cells. J Biol Chem. 1998;273:1568–1573. [PubMed] [Google Scholar]

184. Wheeler DL, Iida M, Kruser TJ, Nechrebecki MM, Dunn EF, Armstrong EA, et al. Epidermal growth factor receptor cooperates with Src family kinases in acquired resistance to cetuximab. Cancer Biol Ther. 2009;8:696–703. [PMC free article] [PubMed] [Google Scholar]

185. Nevo J, Mattila E, Pellinen T, Yamamoto DL, Sara H, Iljin K, et al. Mammary-derived growth inhibitor alters traffic of EGFR and induces a novel form of cetuximab resistance. Clin Cancer Res. 2009;15:6570–6581. [PubMed] [Google Scholar]

186. Huynh HT, Larsson C, Narod S, Pollak M. Tumor suppressor activity of the gene encoding mammary-derived growth inhibitor. Cancer Res. 1995;55:2225–2231. [PubMed] [Google Scholar]

187. Huynh H, Alpert L, Pollak M. Silencing of the mammary-derived growth inhibitor (MDGI) gene in breast neoplasms is associated with epigenetic changes. Cancer Res. 1996;56:4865–4870. [PubMed] [Google Scholar]

188. Specht B, Bartetzko N, Hohoff C, Kuhl H, Franke R, Borchers T, et al. Mammary derived growth inhibitor is not a distinct protein but a mix of heart-type and adipocyte-type fatty acid-binding protein. J Biol Chem. 1996;271:19943–19949. [PubMed] [Google Scholar]

189. Spener F, Unterberg C, Borchers T, Grosse R. Characteristics of fatty acid-binding proteins and their relation to mammary-derived growth inhibitor. Mol Cell Biochem. 1990;98:57–68. [PubMed] [Google Scholar]

190. Hanahan D, Weinberg RA. The hallmarks of cancer. Cell. 2000;100:57–70. [PubMed] [Google Scholar]

191. Huber MA, Kraut N, Beug H. Molecular requirements for epithelial-mesenchymal transition during tumor progression. Curr Opin Cell Biol. 2005;17:548–58. [PubMed] [Google Scholar]

192. Thompson EW, Newgreen DF. Carcinoma invasion and metastasis: A role for epithelial-mesenchymal transition? Cancer Res. 2005;65:5991–5995. [PubMed] [Google Scholar]

193. Basu D, Nguyen TTK, Montone KT, Zhang G, Wang LP, Diehl JA, et al. Evidence for mesenchymal-like sub-populations within squamous cell carcinomas possessing chemoresistance and phenotypic plasticity. Oncogene. 2010;29:4170–4182. [PMC free article] [PubMed] [Google Scholar]

194. Strauss R, Sova P, Liu Y, Li ZY, Tuve S, Pritchard D, et al. Epithelial phenotype confers resistance of ovarian cancer cells to oncolytic denoviruses. Cancer Res. 2009;69:5115–5125. [PMC free article] [PubMed] [Google Scholar]

195. Troussard AA, Mawji NM, Ong C, Mui A, St Arnaud R, Dedhar S. Conditional knock-out of integrin-linked kinase demonstrates an essential role in protein kinase B/Akt activation. J Biol Chem. 2003;278:22374–22378. [PubMed] [Google Scholar]

196. Fuchs BC, Fujii T, Dorfman JD, Goodwin JM, Zhu AX, Lanuti M, et al. Epithelial-to-mesenchymal transition and integrin-linked kinase mediate sensitivity to epidermal growth factor receptor inhibition in human hepatoma cells. Cancer Res. 2008;68:2391–2399. [PubMed] [Google Scholar]

197. Kim SM, Kim JS, Kim JH, Yun CO, Kim EM, Kim HK, et al. Acquired resistance to cetuximab is mediated by increased PTEN instability and leads cross-resistance to gefitinib in HCC827 NSCLC cells. Cancer Lett. 2010;296:150–159. [PubMed] [Google Scholar]

198. Normanno N, Tejpar S, Morgillo F, De Luca A, Van Cutsem E, Ciardiello F. Implications for KRAS status and EGFR-targeted therapies in metastatic CRC. Nat Rev Clin Oncol. 2009;6:519–527. [PubMed] [Google Scholar]

199. De Roock W, Piessevaux H, De Schutter J, Janssens M, De Hertogh G, Personeni N, et al. KRAS wild-type state predicts survival and is associated to early radiological response in metastatic colorectal cancer treated with cetuximab. Ann Oncol. 2008;19:508–15. [PubMed] [Google Scholar]

200. Bardelli A, Siena S. Molecular mechanisms of resistance to cetuximab and panitumumab in colorectal cancer. J Clin Oncol. 2010;28:1254–1261. [PubMed] [Google Scholar]

201. Dunn EF, Iida M, Myers RA, Campbell DA, Hintz KA, Armstrong EA, et al. Dasatinib sensitizes KRAS mutant colorectal tumors to cetuximab. Oncogene. 2010 In press. [PMC free article] [PubMed] [Google Scholar]

202. Hatakeyama H, Cheng HX, Wirth P, Counsell A, Marcrom SR, Wood CB, et al. Regulation of heparin-binding EGF-like growth factor by miR-212 and acquired cetuximab-resistance in head and neck squamous cell carcinoma. PLoS One. 2010;5:e12702. [PMC free article] [PubMed] [Google Scholar]